Phenoxypropanolamine therapeutic agents

ABSTRACT

1. 1-(4-ACETAMIDOPHENOXY) -3 - (2-(4-ACETAMIDOPHENOXY)ETHYLAMINO)PROPAN-2-OL.

United States Patent Oflice 3,845,123 Patented Oct. 29, 1974 3,845,123PI-IENOXYPROPANOLAMINE THERAPEUTIC AGENTS David Alexander Cox,Canterbury, John Christopher Danilewicz, Sandwich, Allan Leslie Ham,Broadstairs, John Edward Glyn Kemp, Canterbury, and Michael Snarey,Sandwich, England, assignors to Pfizer Inc.,

New York, N.Y.

No Drawing. Continuation of abandoned application Ser. No. 98,168, Dec.14, 1970. This application Mar. 28, 1973, Ser. No. 345,726

Claims priority, application Great Britain, Dec. 17, 1969,

61,414/69; May 20, 1970, 24,360/70 Int. Cl. C07c 103/38 U.S. Cl. 260562P 14 Claims ABSTRACT OF THE DISCLOSURE A series of novel substitutedphenoxypropylamine derivatives have been prepared by reacting theappropriate l-phenoxy-Z,3-epoxypropane compound with a suitable organicamine reagent. The resulting l-phenoxy- 3-alkylaminopropan-2-ols areuseful in the field of chemotherapy as anti-angina agents. Preferredmembers include compounds having an acetamido group substituted on thephenyl ring of the phenoxy moiety. Alternate methods of preparation arealso provided.

CROSS REFERENCE This application is a continuation of Ser. No. 98,168,filed Dec. 14, 1970, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to certain new anduseful phenoxypropyl and phenylthiopropyl amine derivatives of principalinterest to those in the field of chemotherapy. More particularly, it isconcerned with various novel substitutedl-phenoxy-3-alkylaminopropan-2-ols and their non-toxic acid additionsalts, which are of especial value in view of their anti-anginaproperties.

In the recent past, several attempts have been made by investigators inthis particular field of therapy to obtain new and still better forms ofagents and/or methods for the treatment of cardiac conditions likeangina pectoris and so on. In many instances, these efforts have furtherinvolved the synthesis and testing of various new and heretoforeunavailable compounds, particularly in the area of the propanolamines.For instance, R. Howe et al. in US. Pat. No. 3,408,387 disclose a seriesof aminoaryloxyalkanolamines in this category, including compounds like1-(4-acetamidophenoxy) 3 (2 phenoxyethylamino) propan-Z-ol, which arereported to be useful as antihypertensive agents, in addition topossessing B-adrenergic blocking properties. However, little is knownabout the effect of other alkanolamines in this area, such as thosecompounds which differ from the aforesaid prior art by having anadditional polar group in the previously unsubstituted phenyl ring ofthe 2-phenoxyethylamino moiety.

SUMMARY OF THE INVENTION In accordance with the present invention, ithas now been rather surprisingly found that certain novel 1- phenoxyand1-phenylthio-3-alkylamino-propan 2 01 compounds are extremely usefulwhen employed in the field of drug therapy as cardiospecific anti-anginaagents. The novel compounds of this invention are all selected from thegroup consisting of phenoxypropanolamine bases of the formula:

and the pharmaceutically acceptable acid addition salts thereof, whereinR is a member selected from the group consisting of alkanoylamino havingfrom one to six carbon atoms, N-methyl-N-alkanoylamino and N-ethyl-N-alkanoylamino each having from two to six carbon atoms in the alkanoylmoiety, chloroacetylamino, trifiuoroacetylamino, acryloylamino,benzoylamino, toluoylamino, chlorobenzoylamino, nitrobenzoylamino,furoylamino, phenylalkanoylamino having up to three carbon atoms in thealkanoyl moiety, succinoylimino, phthaloylimino, carbamoyl,N-monoalkylcarbamoyl and N,N-dialkylcarbamoyl each having up to threecarbon atoms in the alkyl moiety, N-phenylcarbamoyl,N-phenylalkylcarbamoyl having up to three carbon atoms in the alkylmoiety and alkoxycarbonylamino having from one to six carbon atoms inthe alkoxy moiety; n is an integer of from zero to two; R is a memberselected from the group consisting of hydrogen, allyl, alkyl and alkoxyeach having from one to six carbon atoms, fluorine, chlorine andbromine; R is a member selected from the group consisting of hydrogenand alkanoyl having from two to six carbon atoms; R; is a memberselected from the group consisting of hydrogen, alkyl having from one tosix carbon atoms and phenylalkyl having up to three carbon atoms in thealkyl moiety; R is a member selected from the group consisting ofarylalkyl and aryloxyalkyl each having up to four carbon atoms in thealkyl moiety with said aryl group being chosen from the group consistingof alkanoylaminophenyl and alkanoylaminomethylphenyl each having fromone to six carbon atoms in the alkanoyl moiety, carbamoylphenyl,carbamoylmethylphenyl, N- monoalkylcarbamoylphenyl andN,N-dialkylcarbamoylphenyl each having up to three carbon atoms in thealkyl moiety, N-phenylcarbamoylphenyl, and N-phenylalkylcarbamoylphenylhaving up to three carbon atoms in the alkyl moiety; and X is oxygen orsulfur. These novel phenoxypropanolamine compounds all possess strongadrenergic blocking activity, particularly with respect to their effecton myocardial ;8-receptors rather than peripheral B-receptors (i.e.,those affecting vascular, tracheal or bronchial tissue). They aretherefore useful in the treatment of cardiac conditions, such as anginapectoris and cardiac arrhythmia, without adversely affecting bloodpressure or lung or bronchial conditions in afilicted subjects.

Of especial interest in this connection are the preferred compounds ofthe present invention where R(CH in the aforesaid structural formula isspecifically located at the 4-position of the phenyl ring and ispreferably alkanoylamino or alkanoylaminomethyl as previously defined(and most preferably, it is acetamido or acetamidomethyl), R is hydrogenor it is allyl or alkyl having from one to six carbon atoms at the2-position of the phenyl ring, R and R are each hydrogen, R isalkanoylaminophenoxyethyl having from one to six carbon atoms in thealkanoyl moiety (and most preferably, 4-acetamidophenoxyethyl), and X isoxygen. Typical member compounds of the preferred class include such1-phenoXy-3- (Z-phenoxyethylamino)propane-Z-ols as1-(4-acetamidophenoxy)-3-[2-(4-acetamidophenoxy) ethylamino1propan-2-ol,

1- (4-acetamidomethylphenoxy) -3- [2- (4-acetamidophenoxy)ethylamino1propan-2-ol,

1- (2-methyl-4-acetamidophenoxy) '3- [2- (4-acetamido phenoxyethylamino] propan-Z-ol,

1-(2-methyl-4-acetamidomethylphenoxy)-3-[2-(4-acetamidophenoxy)ethylamino]propan-Z-ol, and

1-(2-ally1-4-acetamidophenoxy)-3-[2-(4-acetamidophenoxy)ethylamino1propan-2-ol,

respectively. These particular compounds are all highly potent asregards their selective fl-adrenergic blocking activity, i.e., they showa high degree of selectivity for heart tissue as compared to lungtissue, etc., in addition to possessing the ability to block myocardialfl-receptors to a very high degree.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the processemployed for preparing the novel compounds of this invention, anappropriately substituted 1-phenoxy-2,3-epoxypropane or the thiophenoxyanalog thereof is reacted with a suitable organic amine reagent of theformula R R NH, where R and R are each as previously defined to form thedesired phenoxypropanolamine( or thiophenoxypropanolamine) finalproduct, in which case R is always hydrogen. This particular reaction isnormally carried out in the presence of a reaction-inert polar organicsolvent such as a lower alkanol like methanol or ethanol, or a lowerN,N- dialkylalkanolamide such as N,N dimethylformamide, N,Ndimethylacetamide, N,N diethylformamide and so on. In general, thereaction is conducted at a temperature that is in the range of fromabout C. up to about 100 C. for a period of about one hour to aboutseven days (e.g., 1 hour at 100 C. or 7 days at 20 C.). It should benoted that the epoxy starting materials employed in this reaction are,for the sake of time and convenience, most readily obtained from thecorresponding phenols or thiophenols, as the case may be, by usingstandard organic procedures Well known to those skilled in the art forthe reaction of phenols with 2,3-epoxypropyl chloride. For instance, thereaction can be carried out in aqueous alkali at ambient temperatures,followed by extraction into a suitable organic solvent such asdichloromethane and recovery of the desired product from said solventextract by conventional means.

Alternate methods of preparation for the compounds of this inventioninvolve (l) reacting a suitable organic amine reagent of the formula R RNH with a chlorohydrin or bromohydrin or an ether thereof (where R isalkyl rather than hydrogen) corresponding in structure to the2,3-epoxide previously employed; and (2) reacting the appropriatephenoxyor phenylthiopropanolamine reagent or an ether derivative thereofwith a suitable alkyl chloride or bromide of the formula R X, wherein Ris defined as aforesaid and X is halogen like chlorine or bromine. Inboth instances, these particular routes are carried out by firstdissolving the key reactants in a mutual solvent, such as methanol orethanol, which must also preferably contain a suitable amount of alkalireagent like sodium bicarbonate or else excess amine reactant, and thenheating the entire mixture together, while under reflux conditions,until the reaction is essentially complete in each case. Additionally,the same reaction can also be carried out in either (1) or (2) by simplyheating the two reactants together in equimolar proportions when in theabsence of a solvent.

To prepare compounds of the invention where R, is arylalkyl oraryloxyalkyl which contains a branched-chain alkyl moiety (e.g., anappropriately substituted Z-phenoxyl-methylethyl group), a preferredmethod of synthesis involves condensing an appropriately substitutedpehnoxypropanolamine reagent where R; is hydrogen with a correspondingarylalkyl or aryloxyalkyl ketone (e.g. an appropriately substitutedphenoxyacetone) to form the desired Schiffs base, which is thereafterhydrogenated in the presence of a catalyst like platinum or reduced withsodium borohydride to yield the desired 1-phenoxy-3-alkylaminopropan-Z-ol final product as previously defined. In this way,a propanolamine starting material like 1-(4-acetamidophenoxy)-3-aminopropan-2-ol is converted to1-phenoxy-S-alkylaminopropan-Z-ol final products such as 1-(4-acetamidophenoxy) -3- [2- (Z-acetamidophenoxy) 1- methylethyl amino]propan-Z-ol,

1- (4-acetamidophenoxy) -3- [2- (4-carbamoylphenoxy 1- methylethylamino]prop an-2- 01,

4 l- 4-acetamidophenoxy -3- 2- (4-acetamidophenoxy) 1- methylethylamino]propan-Z-ol, and l- (4-acetamidophenoxy) -3- [2- Z-carbamoylphenoxy)lmethylethylamino] propan-Z-ol in a most facile manner.

As regards phenoxypropanolamine compounds of the invention where R onthe phenyl ring of the phenoxy or thiophenoxy moiety is specificallyacylamino (e.g., acetamido and the like), these are alternately and mosteasily prepared by subjecting the corresponding nitro compounds (i.e.,where R on the phenyl ring is nitro) to catalytic hydrogenation,followed by acylation of the resulting amino group to yield the desiredcarboxamide final product. In this way, the amino compound serves as anintermediate f r the preparation of other final products of thisinvention that can subsequently be derived therefrom. For instance,acylation with acetic anhydride leads to the acetamido compounds, whilethe use of acryloyl chloride, on the other hand, affords thecorresponding acryloylamino final products.

Needless to say, compounds of the invention in which R is alkyl of fromone to six carbon atoms (i.e., ether derivatives) can also be preparedfrom compounds of the invention where R is simply hydrogen by merelysubjecting the latter unsubstituted phenoxypropanolamine per se toconventional alkylation procedures well known to those skilled in theart. In like manner, the esters of those compounds having free hydroxygroups (where R is again hydrogen) can also be prepared by conventionalprocedure, starting from the aforesaid phenoxypropanolamines per se andusing standard esterification techniques to achieve the desired estersof this invention where R is alkanoyl having from two to six carbonatoms, provided that R is not hydrogen. On the other hand, to obtain anester in which R is hydrogen, one must first start with a compound inwhich R is other than hydrogen and is pref erably a blocking group, suchas benzyl, which is easily removable without affecting the esterlinkage.

Inasmuch as the phenoxypropanolamine compounds of this invention allpossess at least one asymmetric center, they may exist in separated dandloptically active forms, as well as in racemic dl-mixtures necessarilyproduced by the various synthetic methods just previously described. Theinvention, of course, includes the d-, and land racemic forms all wellwithin its scope. For instance, an optically active isomer may beobtained by simply resolving the racemic mixture using standardtechniques well known to those skilled in the art, e.g., by fractionalcrystallization of an acid addition salt derived from an opticallyactive acid.

Needless to say, compounds of the invention which have two asymmetriccenters also exist as two racemic pairs of diastereoisomers, and theseracemic pairs can generally be separated from one another using columnchromatog raphy and/or other standard techniques well known to thoseskilled in the art. Here again, the invention includes well within itsscope the separate pairs of isomers and mixtures thereof, as the d-,land racemic forms all as previously mentioned.

The pharmaceutically acceptable acid addition salts of thephenoxypropanolamine base compounds of this invention are prepared bysimply treating the corresponding organie bases with mineral and organicacids which form non-toxic acid addition salts having pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate,fumarate, lactate, tartrate, citrate, gluconate, saccharate,methanesulfonate, benzenesulfonate and p-toluenesulfonate salts.

As previously indicated, the phenoxypropanolamine compounds of thisinvention are of especial value therapeutically when employed asanti-angina agents, particularly in view of their ability to blockmyocardial fl-adrenergic receptor sites in cardiac-afllicted subjects toa sta;

tistically significant degree. For instance, l-(2-methyl-4acetamidophenoxy) 3-[2-(4 acetamidophenoxy)ethylaminolpropan-Z-ol, atypical and preferred agent of the present invention, has been found toexert its highly selective B-adrenergic blOcking effect in consciousdogs to a statistically significant degree, with respect to hearttissue, when given by the oral route of administration with out showingany substantial signs of toxic side effects. The other compounds of thisinvention also cause similar results. Furthermore, all the hereindescribed compounds of this invention can be administered by either theoral or parenteral routes of administration, for the present purposes athand, without causing any significant untoward pharmacological sideeffects to occur in the subject to whom they are so administered. Ingeneral, these compounds are ordinarily administered at oral dosagelevels ranging from about 0.05 mg. to about 4.0 mg. per kg. of bodyweight per day, although variations will necessarily occur dependingupon the weight and condition of the subject being treated and theparticular route of administration chosen.

In connection with the use of the phenoxypropanolamine compounds of thisinvention for the treatment of cardiac-afllicted subjects, it is to benoted that these compounds may be administered alone, but generally willbe administered in combination with a pharmaceutical carrier. Thecarrier is normally selected with regard to the intended route ofadministration as well as standard pharmaceutical practice. For example,these compounds may be administered orally in the form of tabletscontaining excipients such as starch or lactose, or in capsules eitheralone or on admixture with excipients, or else in the form of elixirs orsuspensions containing flavoring agents or coloring matter, etc. Forpurposes of parenteral administration, they are best used in the form ofa sterile aqueous solution of a previously enumerated water-soluble acidaddition salt, which solution may also contain sufficient saline orglucose to render the final composition isotonic. These particularaqueous solutions are especially suitable for intravenous, intramuscularand subcutaneous injection purposes.

The activity of the compounds of the present invention, as anti-anginaagents, i.e., as selective fl-adrenergic blockers, is determined bytheir ability to selectively block myocardial fi-receptors rather thanperipheral B-receptors as previously discussed, based on any one or moreof the following standard biological/ or pharmacological tests, viz.,(l) by measuring and comparing the inhibition of catecholamine-inducedchanges in isolated guinea-pig atria and trachea; (2) by measuring andcomparing suppression of tachycardia and relaxation of the tracheainduced by isoprenaline in the anesthetized guinea-pig; (3) by measuringthe suppression of the tachycardia induced by isoprenaline in theanesthetized cat or conscious dog, and (4) by measuring and comparingsuppresion of the stimulating action of isoprenaline on the adenylcyclase enzyme present in rat heart and lung tissue.

In test (1), the isolated guinea-pig atria and trachea, in controlledphysiological liquid environments, are stimulated electrically and theeffects of adding increasing amounts of adrenaline to the liquidenvironment, on both the rate and force of contraction of the atria, andof isoprenaline on the degree of relaxation of the trachea, are thenmeasured. The test compound is then added to the liquid environment atvarious concentration levels, and the elfects of adding adrenaline andisoprenaline, respectively, are measured once again. The concentrationsof test compound which give a 50% inhibition of the effects ofadrenaline and isoprenaline are then calculated, and taken as a measureof activity of the compound per se with regard to inhibition ofmyocardial and peripheral [3- receptors, respectively.

In test (2), blood pressure, heart rate and pressure within a segment ofthe trachea of a guinea-pig anesthetized with sufficient sodiumpento'barbitone to prevent spontaneous respiration are measured, whileartificial respiration is maintained directly into the lung at aconstant rate. Isoprenaline, at a standard dose of 0.5 ,ug., is theninjected intravenously to induce tachycardia and to cause relaxation ofthe trachea and lower blood pressure. The ability of the test compoundto suppress the tachycardia, and/or antagonize the relaxation of thetrachea, and/ or inhibit the fall in blood pressure caused by theisoprenaline is then measured by repeating the procedure, but this timeinjecting the test compound prior to the isoprenaline administration.

In test (3), chloralosed cats are dosed with the test compoundintravenously at levels ranging from 0.1 mg. to 1.0 mg. per kg. of bodyweight, respectively, and the elfect of an isoprenaline challenge onheart rate is measured. Heart rates are recorded both before closing andat a 30- minute period thereafter, and the cats are then given asubcutaneous challenge of isoprenaline. The degree ofisoprenaline-induced tachycardia is recorded at 15-minute intervals.Conscious dogs are also employed in such tests, with the test compoundbeing administered intravenously at dose levels ranging from 0.125 to0.25 nag/kg. and orally at 0.5 to 4 mg./kg., respectively.

In test (4), homogenized rat heart in a standardized medium, with andwithout isoprenaline, is incubated with adensosine-S-triphosphoric acid(ATP) labelled with tritium. The test compound is then added at variousconcentration levels to the homogenate containing the isoprenaline.After incubation at 30 C., cyclic-3,5-adenosine-monophosphoric acid(cyclic-AMP), containing a known proportion of carbon-l4 labellelmaterial, is added and the synthesis of cyclic-AMP by the adenylcyclaseenzyme is stopped by raising the temperature. Cyclic-AMP is thenseparated and purified, and the amount synthesized in each case by theenzyme is measured as its tritium to carbon-14 ratio. The concentrationof test compound which gives a 50% inhibition of the stimulating etfectof isoprenaline on cyclic-AMP synthesis is taken as a measure of itsactivity. In order to assess the degree of tissue selectivity of theagent, the procedure is repeated using homogenized rat lung and theresults obtained in this manner are compared with those previouslyreported for the homogenized rat heart.

Although the physician will ordinarily decide the proper dosage range atwhich these compounds are to be administered to humans, it is expectedthat for the treatment in man of cardiac conditions, such as anginapectoris, the preferred compounds of the invention will generally beadministered orally at a level in the range from 0.5 to 4.0 mg. per kg.per day, divided in 3 or 4 daily doses, and that dosages for intravenousadministration will generally be about one-tenth of these in a singledaily dose. Thus, for a typical adult patient of about 70 kg. bodyweight, individual tablets or capsules might contain from 10 to 50 mg.of active ingredient and intravenous dosages would ordinarily containfrom 1.0 to 20 mg. of said ingredient, in either case, combined in asuitable vehicle or carrier.

EXAMPLE I A solution consisting of 13 g. of1-(4-acetamidophenoxy)-3-aminopropan-2-ol and 10 g. ofZ-acetamidophenoxyacetone dissolved in 75 ml. of ethanol was heatedunder reflux for a period of two hours. Upon completion of this step, acatalytic amount (0.3 g.) of platinum oxide was added to the cooledmixture, and the latter was subsequently hydrogenated at 20 C. and 1,100p.s.i. pressure of hydrogen. After the hydrogen uptake had ceased, thecatalyst was removed by means of filtration and the filtratesubsequently evaporated in vacuo to alford a yellow semi-solid product.The latter material was then dissolved in chloroform and extracted withaqueous hydrochloric acid, followed by basification of the aqueous layerand re-extraction into chloroform prior to filtering. Upon The proceduredescribed in Example I was repeated, except that4-carbamoylphenoxyacetone was employed as starting material in place ofZ-acetamidophenoxyacetone, using the same molar proportions as before.In this particular case, the corresponding final product thus obtainedwas 1 (4acetamidophenoxy)-3-[2-(4-carbamoylphenoxy))-l-methylethylamino]propan-2-ol,ultimately isolated as the oxalate salt, m.p. 142 C.

Analysis.Calcd. for C21H27N305'C2H204: C, H, 5.94; N, 8.56. Found: C,56.32; H, 6.24; N, 8.50.

EXAMPLE III The procedure described in Example I was repeated exceptthat Z-carbamoylphenoxyacetone was employed as starting material inplace of the corresponding 2-acetamido compound, using the same molarproportions as before. In this particular case, the corresponding finalproduct thus obtained was l-(4-acet-amidophenoxy)-3-[2-(Z-carbamoylphenoxy) 1 methylethylamino]propan-2- ol, ultimatelyisolated as the hemifumarate hemihydrate, m.p. 97-99 C.

AnalySiS.Ca1Cd. for C21I'I27N3O51/2C4H4O4"%H20I C, 58.80; H, 6.45; N,9.05. Found: C, 59.16; H, 6.52; N, 8.95.

EXAMPLE IV The procedure described in Example I was repeated exactly,except that 4-acetamidophenoxyacetone was employed as starting materialin place of the corresponding 2-acetamido compound In this particularcase, the corresponding final product thus obtained was1-(4-acetamidophenoxy)-3-[2-(4-acetamidophenoxy) 1methylethylamino]propan-2-ol, isolated as the free base, m.p. 165- 167C.

Analysis.Ca1cd. for C H N O C, 63.59; H, 7.04; N, 10.11. Found: C,63.88; H, 6.91; N, 10.31.

EXAMPLE V A mixture consisting of 5.3 g. 1-(4-acetamidophenoxy)-3-aminopropan-2-ol and 2.0 g. of 1-bromo-2-(4-acetamidophenoxy)ethanewas heated at 140 C. for a period of three hours. At the end of thistime, the resultant solid material formed from the reaction mixture wassuspended in aqueous sodium carbonate solution, filtered and theresulting filter cake recrystallized once from water. After a furtherrecrystallization from ethanol, there was ultimately obtained 0.25 g. of1-(4-acetamidophenoxy)-3-[2- (4-acetamidophenoxy)ethylaminoJpropan-2-ol,m.p. 193- 194 C.

Analysis.Calcd. for C H N O C, 62.82; H, 6.78; N, 10.47. Found: C,62.33; H, 6.76; N, 10.32.

EXAMPLE VI The procedure described in Example V was repeated except that1-bromo-2-(Z-carbamoylphenoxy)ethane was employed as starting materialin place of 1-b'romo-2-(2- acetamidophenoxy)ethane, using the samemolar'proportions as before. In this particular case, the correspondingfinal product thus obtained was 1-(4-acetamidophenoxy)- 3- [2-(Z-carbamoylphenoxy) ethylamino1propan-2-ol, ultimately isolated as thehemifumarate salt, m.p. 123 C.

8 Analysis.--Calcd. for C H N O /2C H O' C, 59.31; H, 6.12; N, 9.43.Found: C, 59.01; H, 6.06; N, 6.45.

EXAMPLE VII A solution consisting of 5.6 g. of1-(4-acetamidophenoxy)-2,3-epoxypropane and 4.9 g. of2-(4-carbamoylphenoxy)ethylamine dissolved in ml. of ethanol was stirredat ambient temperatures for a period of three days. At the end of thistime, the resulting precipitate was recovered from the mixture by meansof suction filtration and recrystallized from aqueous ethanol to aiford5.4 g. of pure 1-(4-acetamidophenoxy)-3-[2-(4-carbarnoylphenoxy)ethylamino]propan-2-ol in the form of a white crystalline solid,m.p. -177 C.

Analysis.Calcd. for C H N O C, 62.00; H, 6.50; N, 10.85. Found: C,61.83; H, 6.39; N, 11.18.

EXAMPLE VIII The procedure described in Example VII was repeated toprepare the following 1-phenoxy-3-(Z-phenoxyethylamino)propan-2-olcompounds, starting from the appropriate 1-phenoxy-2,3-epoxypropane andthe corresponding 2-phenoxyethylamine reagent in each case:

1- (4-acetamidophenoxy)-3- [2 (4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 198-200 C.

1- 4-propionamidophenoxy) -3- [2- 4-carbamoylphenoxy) ethylaminopropan-2-o1, m.p. 187-189 C.

1- 4-propionamidophenoxy) -3- [2- (4-acetamidophenoxy) ethylamino]propan-Z-ol, m.p. 203 C.

1- 2-methyl-4-acetamidophenoxy -3- [2- 4-acetamidophenoxy) ethylamino]pr0pan-2-ol, m.p. 178-180 C.

1- (4-acetamidomethylphenoxy) -3- [2- (4-acetamidophenoxy) ethylamino]propan-2-ol, m.p. 176-177 C.

1- (4n-butyramidophenoxy) -3 [2- (4-acetamidophenoxy)ethylamido]prop-an-2-ol, m.p. 206-207 C.

1- 3-methyl-4-acetamidophenoxy-3- [2-(4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 144-146 C.

1-(4-carbamoylmethylphenoxy) -3- 2-(4-acetamidophenoxy ethylamino]propan-2-ol, m.p. -192 C.

1- (4-isobutyramidophenoxy) -3- [2- (4-acetamidophenoxy) ethylamino]propan-2-ol, m.p. 219-220 C.

1- (2-methyl-4-acetarnidophenoxy) -3- [2-(4-carbamoylphenoxy)ethylamino] propan-2-ol, m.p. 18 1-182 C.

1- [4- (Z-ethoxycarbonylamino phenoxy] -3- [2-(4-acetamidophenoxy)ethylamino] propan-2-ol, m.p. 166- 168 C.

1- [4- Z-acetamidoethyl) phenoxy] -3- [2- (4-carbamoylphenoxy)ethylamino] propan-Z-ol, m.p. 170-173 C.

1- (3-methyl-4-acetamidophenoxy) -3- [2- (4-carbamoylphenoxy)ethylamino] propan-2-ol, m.p 168-171 C.

1- [4- (2-ethoxycarbonylamino) -phenoxy] -3- [2- (4-carbamoylphenoxy)ethylamino] propan-Z-ol, m.p. 176-178 C.

1- [4- (N-methylcarbamoyl phenoxy] -3- [2- (4-acetamidophenoxyethylamino] propan-2-ol monohydrate, m.p. 196-198 C.

1- [4- Z-acetamidoethyl) phenoxy] -3- 2- (4-acetamidophe noxy)ethylamino] propan-Z-ol, m.p. 174-175 C.

1- 4-methoxycarbonylamino phenoxy-3- [2- (4-acetamidophenoxy)ethylamino]propan-Z-ol, m.p. -197 C.

1-(2-methoxy-4-acetamidomethy1phenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino] prop an-2-ol, m.p. 162- 164 C.

1- [4- (N-methylacetamidophenoxy) ]-3- [2- (4-acetamidophenoxyethylamino prop an-2-ol, m.p. 77-80 C.

1-(4-acetamidomethylphenoxy) -3- [2- (4-carbamoylphenoxy)ethylamino]propan-2-o1, m.p. 177 C.

1- S-acetamidomethylphenoxy) -3 [2- (4-carbamoylphenoxy) ethylamino]propan-2-o1, m.p. 142-144 C.

1- (4-carbamoylmethylphenoxy) -3- 2- (4-carbamoylphenoxy) ethylamino]propan-Z-ol, m.p. 194-196 C.

1- (4-acetamidophenoxy) -3- [2- (4-propionamidophenoxy) ethylamino]propan-Z-ol, m.p. 204-205 C.

1- [4- (N-methylcarbamoyl phenoxy] -3- [2- (4-carbamoylphenoxy)ethylamino] propan-Z-ol, m.p. 17 6-177 C.

1- 4-acetamidophenoxy) -3 [2-3-methyl-4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 143-114 C.

1- (4-propionamidomethylphenoxy) -3- [2-(4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 171-173 C.

1- (4-formamidophenoxy) -3- 2- (4-acetamidophenoxy)ethylaminoJpropan-Z-ol, m.p. 153-155 C.

1- 2-carbamoylphenoxy) -3 [2-(4-carbamoylphenoxy)ethylamino]propan-2-ol, m.p. 178-180 C.

1-(4-acetamidomethylphenoxy) -3- [2-(4-carbamoylmethylphenoxy)ethylamino1propan-2-ol, m.p. 190-191 C.

1- (2-acetamidophenoxy-3 [2- (4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 159-160 C.

1 (4-formamidomethylphenoxy) -3- [2-(4acetamidophenoxy)ethylamino]propan-2-ol, m.p. 158-160 C.

1-(4-acetamidomethylphenoxy)-3-[Z-(Z-acetamidophenoxy)ethylamino]propan-2-ol,m.p. 165166 C.

1-(2-rnethyl-4-acetamidomethyl -3- [2-(4-acetamidophenoxy)ethy1amino]propan-2-ol monohydrate, m.p. 104- 106 C.

1- (4- acetamidophenoxy) -3- [2-(4-carbamoylmethylphenoxy)ethylamino]propan-2-ol, m.p. 196197 C.

1-( 2-methoxy-4-acetamidomethylphenoxy) -3- [2- (4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 150- 152 C.

1- (4-acetamidophenoxy) -3- [2-(4-acetamidomethylphenoxy)ethylaminoJpropan-Z-ol, m.p. 171-173 C.

1- 4-acetamidomethylphenoxy) -3- [2-(4-acetamidomethylphenoxy)ethylamino]propan-2-ol, m.p. 187-188 C.

l-(2-allyl-4-acetamidophenoxy) -3- [2-(4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 147-149 C.

1- (4-acetamidomethylphenoxy) -3- [2-(4-propionamidophenoxy)ethylamino]propan-2-ol, m.p. 185-187 C.

1-(4-carbamoylphenoxy)-3-[2-(4-acetamidophenoxy) ethylamino1propan-2-ol,m.p. 138-141 C.

1- 2-chloro-4-acetamidophenoxy) -3- [2-(4-acetamidophenoxy)ethylamino]propan-2-ol, m.p. 186-188 C.

1- (4-acetamidophenoxy) -3- [2- (2-acet amidophenoxy)ethylamino]propan-2-ol, m.p. 152-154 C.

1- (4-acetamidophenoxy) -3- [2- (4-formamidophenoxy)ethylamino]propan-2-ol, m.p. 154-156 C.

EXAMPLE IX The following 1 phenoxy-3-phenoxyalkylaminopropan-2-olcompounds are prepared according to the procedure of Example VII,starting from the appropriate 1- phenoxy 2,3 epoxypropane and thecorresponding phenoxyalkylamine reagent in each instance:

10 EXAMPLE x A solution consisting of 12 g. of 1-(3-nitrophenoxy)- 3 [2(4 carbamoylphenoxy)ethylamino]propan-2 ol (m.p. 127-129 C.) dissolvedin 1000 ml. of methanol was subjected to catalytic hydrogenation over0.3 g. of platinum oxide at room temperature (-25 C.) and 50 p.s.i.pressure of hydrogen [the 3-nitro starting material was preparedaccording to the procedure of Example VII from 1 (3nitrophenoxy)-2,3-epoxypropane and 2-(4- carbamoylphenoxy) ethylamine].Upon completion of this step, the resultant mixture was filtered and theclear filtrate thereafter evaporated to dryness while under reducedpressure to afford a white residual solid. Recrystallization of thelatter material from methanol then gave pure 1 (3aminophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol, m.p.149-157 C.

An aqueous mixture consisting of 10 g. of 1-(3-aminophenoxy) 3[2-(4-carbamoylphenoxy)ethylamino1propan-Z-ol in 150 ml. of water wasadjusted to pH 4-5 with dilute hydrochloric acid and then stirredvigorously for several minutes in order to effect complete solution. Atthis point, 3 g. of acetic anhydride were added to the mixture in adropwise manner and the pH of the resulting solution was simultaneouslymaintained within the aforestated pH range by means of dilute aqueoussodium hydroxide. After further stirring the spent reaction mixture fora period of one hour, it was subsequently basified with additionaldilute aqueous sodium hydroxide solution and the resulting solidprecipitate which formed at this point was thereafter collected by meansof suction filtration to give 1-(3-acetamidophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan 2 01 as a white crystallinebase, m.p. 164-165 C. The analytical sample was then recrystallized fromaqueous ethanol, but the melting point remained constant.

Analysis.Calcd. for C H N O C, 62.00; H, 6.50; N, 10.85. Found: C,61.82; H, 6.44; N, 10.74.

EXAMPLE XI The procedure described in Example X was repeated except that1-(3-nitrophenoxy) 3 [2-(4-acetamidophenoxy)ethylamido]propan-2-ol (m.p.107-109 C.) was employed as starting material instead of1-(3-nitrophenoxy)- 3- [2- (4-carbamoylphenoxy) ethylamino] propan-Z-ol,using the same molar proportions as before with respect to the keyacylation step. In this particular case, 1-(3-nitrophenoxy)-3-[2-(4acetamidophenoxy) ethylamino]propan-2- 01 [prepared according to ExampleVII from 1-(3-nitrophenoxy)-2,3-epoxypropane and 2-(4-acetamidophenoxy)ethylamine] was converted to 1-(3-aminophenoxy)-3-[2- (4acetaminophenoxy)ethylamino]propan-Z-ol which, in turn, gavel-(3-acetamidophenoxy) 3 [2-(4-acetamidophenoxy)ethylamino1propan-2-olon treatment with acetic anhydride. The product was ultimately isolatedas the hydrochloride salt, mp. 237-239 C.

Analysis. CalCd. for C21H27N305'HC1: C, H, 6.64; Cl, 8.08; N, 9.60.Found: C, 57.53; H, 6.77; CI, 8.19; N, 9.33.

EXAMPLE XII The procedure described in Example X was repeated againexcept that1-(4-nitrophenoxy)-3-[2-(4-acetamidophenoxy)ethylamino]propan-2-ol (m.p.179-181 C.) was employed as starting material instead of1-(3-nitrophenoxy)-3- [2-(4 carbamoylphenoxy)ethylamino1propan-2- 01 andacryloyl chloride was the acylating agent of choice rather than aceticanhydride (using the same molar proportions, of course). In thisparticular case, 1-(4-nitrophenoxy-3 [2-(4acetamidophenoxy)ethylamino1propan- 2-01 [prepared according to ExampleVII from l-(4-nitrophenoxy) 2,3 epoxypropane and2-(4-acetamidophenoxy)ethylamine] was converted to 1-(4-aminophenoxy)- 3[2 (4 acetamidophenoxy)ethylamino1propan 2 01 which, in turn, gavel-(4-acryloylamidophenoxy)-3-[2- (4-acetamidophenoxy)ethylamino1propan 201 on treatment with acryloyl chloride. The product was ultimatelyisolated as the hydrochloride salt, m.p. 24l243 C.

Analysis. -Calcd. for C22H2'fN30'5'HC1: C, H, 6.27; N, 9.43. Found: C,58.62; H, 6.09; N, 9.17.

EXAMPLE XIII The following l-phenoxyandl-phenylthio-3-alkylaminopropan-Z-ol compounds are prepared by employingthe procedures described in the previous examples, starting from readilyavailable materials in each instance:

and the chloroform extract is thereafter washed with Water and driedover anhydrous sodium sulfate prior to concentration in vacuo. The crudeproduct obtained in this manner is then recrystallized from ethanol toafford pure 1 (2 methyl 4 acet-amidophenoxy) 3 {N [2 s (4acetamidophenoxy)ethyl] N benzyl-amino}-2-acetoxypropane. On subsequenttreatment with hydrogen in the presence of palladiu-m-on-carbon, thelatter compound then gave 1 (2 methyl 4-acetamidophenoxy)-3-[2- (4-acet-amidophenoxy) ethylamino] -2-acetoxypropane.

In like manner, 1-(4-acetamidophenoxy)-3-{N-[2-(4- acetamidophenoxy)ethyl-N-benzylamino}propan 2 ol is converted to1-(4-acetamidophenoxy)-3-N-[2-(4-acetamidophenoxy)ethyl=amino]-2-propionoxypropane on treatment with propi-onic acid anhydride in thepresence of pyridine, followed by hydrogenolysis; and1-(4-acetamidomethylphenoxy) 3 {N [2 (4 -'acetamidophenoxy)-ethyl]-N-benzylamino}propan-2-ol is converted to 1-(4-acetamidomet'hylphenoxy) 3 N [2 (4actemidophenoxy)ethylamino]-2-(n-capronoxy)propane on treatment withcaproic acid anhydride in the presence of pyridine, followed byhydrogenolysis. Other esters of this inventi'on (i.e., compounds Where Rin the structural formula is alkanoyl as previously defined) aresimilarly prepared.

EXAMPLE XV The non-toxic hydrohalide acid addition salt-s of each of thel-phenylthioand 1-phenoxy-3-alkylaminopropan- 2-01 base compounds ofthis invention reported previously, such as the correspondinghydrochloride, hydrobro-rnide and hydriodide salts, are eachindividually prepared by first dissolving the respective organic basecompound in absolute ether and then adding a saturated solution of theappropriate hydrohalide gas in ethyl acetate to the aforementionedethereal solution, Whereupon the desired acid addition salt soonprecipitates from said solution. In this way, 5.0 g. of1-(Z-methyl-4-acetamidophenoxy)3-[2-(4- EXAMPLE XIV Two grams of1-(2-rnethyl-4-acetamidophenoxy)-3-{N- [2 (4 acetamidophenoxy) ethyl]N-benzyl amino}propan-2-ol are added to 20 ml. of anhydrous pyridine,followed by the immediate addition of 8.0 g. of acetic anhydride to themixture with stirring. The resulting solution is then refluxed for aperiod of |five minutes, cooled and subsequently poured into ml. of iceWater. The latter aqueous solution is then basified with 2N aqueoussodium hydroxide solution and extracted with chloroform,

aforementioned l-phenylthioand l-phenoxy 3 alkylaminopropan-Z-ol basecompounds reported previously are each prepared by dissolving the propermolar amounts of the respective acid and base in separate portions ofethanol and then mixing the two solutions together, followed by theaddition of diethyl ether to the resultant mixture in order to effectprecipitation of the desired acid addition salt therefrom. In thismanner, equimolar amounts of 1 (2 methyl-4-acetamidophenoxy)-3-[2-(4-acetamidophenoxy)ethyl=amino]propan-Z-ol and concentrated sulfuric acidreact to afford the corresponding sulfuric acid addition salt. In likemanner, each of the other salts is also similarly prepared.

What is claimed is:

1. 1 (4 acetamidophenoxy) 3 [2 (4 acetamidophenoxy)ethylamino]prop-an-Z-ol.

2. 1 (4 acetamidomethylphenoxy) 3 [2 (4- acetamidophenoxy ethylamino]propan-Z-ol.

3. 1 (2 methyl 4 acet-amidophenoxy) 3 [2 (4acetamidophenoxy)ethylamino]propan-2-ol.

4. 1 (2 methyl 4 acetamidomethylphenoxy) 3[2-(4-acetamidophenoxy)ethylamino]propan-2-ol.

5. 1 (2 allyl 4 acet-amidophenoxy) 3 [2 (4acetamidophenoxy)ethylamino]propan-Z-ol.

6. A compound selected from the group consisting ofphenoxylpropanolamine bases of the formula and the pharmaceuticallyacceptable acid addition salts thereof, wherein R of R(CH isalkanoyl-amino having from one to six carbon atoms when n is zero and isalkanoylamino having one to three carbon atoms when n is one, said nbeing an integer of from zero to one, inclusive; R is hydrogen, allyl ormethyl, and R is alkanoylaminophenoxyethyl having from one to six carhonatoms in the alkanoyl moiety.

7. A compound as claimed in claim 6 wherein R is alkanoylamino havingfrom one to six carbon atoms and n is zero.

8. A compound as claimed in claim 6 wherein 'R is alkanoyl'amino havingfrom one to three carbon atoms and n is one.

9. A compound as claimed in claim 6 wherein R is hydrogen.

10. A compound as claimed in claim 6 wherein R is allyl.

11. A compound as claimed in claim 6 wherein R is methyl.

12. A compound as claimed in claim 6 wherein R is2-(4-acetamidophenoxy)ethyl.

13. A compound as claimed in claim 7 wherein (R is acetamido.

14. A compound as claimed in claim 8 wherein R is acetamido.

References Cited UNITED STATES PATENTS 3,562,297 2/1971 Howe et al.260-562 3,574,749 4/1971 Howe et a1. 260--562 3,337,628 8/1967 Smith eta1. 260-562 HARRY I. MOATZ, Primary Examiner U .8. Cl. X.R.

260--326 R, 326.5 FM, 347.3, 553 A, 558 'P, 558 D, 562 B, 347.2;424-274, 285, 322, 324

1. 1-(4-ACETAMIDOPHENOXY) -3 -(2-(4-ACETAMIDOPHENOXY)ETHYLAMINO)PROPAN-2-OL.